Brain metastases are an important limiting factor in the successful treatment of patients with non-small cell lung cancer (NSCLC). Despite the standard use of whole brain radiotherapy (WBRT), the prognosis of patients with brain metastases remains dismal. The growth and development of brain metastases is critically dependent on a functional blood supply. Angiogenesis in solid tumors is driven by VEGF via the endothelial growth factor receptor, VEGFR2. VEGFR2 is the major mediator of several physiological and pathological effects of VEGF-A on endothelial cells, including proliferation, survival, migration and permeability. The VEGF signaling pathway as a target in advanced NSCLC has recently been validated in a randomized phase III study of bevacizumab, a monoclonal antibody against VEFG-A, in combination with platinum-based chemotherapy. AZD2171 is an oral, highly potent pan-VEGF receptor tyrosine kinase inhibitor that has been shown to generate significant inhibition of tumor growth in all human tumor xenografts examined, including lung, colon, prostate, ovarian and breast, as well as potentiation of the effects of radiation in lung cancer models. We propose a Phase II study of AZD2171 with concomitant WBRT for new brain metastases in patients with NSCLC. The primary objective of this study is to measure the overall median survival. In order to assess the antiangiogenic effects of AZD2171 in brain metastases from NSCLC, we will conduct serial non-invasive magnetic resonance imaging (MRI) to measure the potential vascular effects of AZD2171 on brain metastases. MRI techniques that will be utilized include dynamic contrast enhanced imaging, arterial spin labeling and perfusion weighted imaging in an effort to detect changes in tumor perfusion, permeability and blood flow. Our institution has recently demonstrated the feasibility and utility of these correlative imaging techniques in patients with glioblastoma, and we are uniquely situated to extend these techniques to the study of AZD2171 in brain metastases. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer deaths in the United States and the most common cancer to spread (metastasize) to the brain. Brain metastases are often fatal, and new therapies are desperately needed. We propose to study AZD2171, an experimental therapy that acts on tumor blood supply, in lung cancer patients with brain metastases.